This invention relates to new chemical compounds. More particularly it relates to new chemical compounds which are of value for use in combination with beta-lactam antibiotics, to increase their effectiveness.
One of the most well-known and widely-used classes of antibacterial agents is the class known as the beta-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the beta-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given beta-lactam antibiotic results because the microorganism produces a beta-lactamase. The latter substances are enzymes which degrade the penicillin or cephalosporin, rendering it inactive as an antibacterial agent. However, certain substances will inhibit beta-lactamase enzymes, and when a beta-lactamase inhibitor is used in combination with a beta-lactamase-susceptible beta-lactam antibiotic, the effectiveness of the beta-lactam antibiotic is increased or enhanced. Such an effect is known as synergy. Synergy is deemed to be exhibited by a combination of a beta-lactamase inhibitor and a beta-lactam antibiotic when the antibacterial activity of the combination is significantly greater than the sum of the antibacterial activities of the individual components.
Thus, the present invention provides certain new chemical substances which are potent inhibitors of bacterial beta-lactamases. More specifically, these new chemical substances are derivatives of penicillanic acid 1,1-dioxide having a disubstituted methyl group at the 6-position, and certain salts and esters thereof. Said disubstituted methyl group is of the formula X--CH--Y, where X is hydroxy, acylated hydroxy or amino and Y is a carboxy group or an esterified carboxy group.
Penicillanic acid 1,1-dioxide itself, sulbactam, is a well-known beta-lactamase inhibitor (U.S. Pat. No. 4,234,579), and 6-(hydroxyalkyl) and 6-(aminoalkyl) derivatives thereof are also known to possess beta-lactamase inhibitory properties (U.S. Pat. Nos. 4,287,181 and 4,452,796. Published British patent application No. 2,053,220 refers in a broad and general way to penicillanic acid 1,1-dioxide compounds, allegedly having beta-lactamase inhibiting properties.